Recent studies have suggested that selective D3 ligands may have therapeutic potential as novel pharmacotherapy for the treatment of drug addiction. Although a number of selective D3 ligands have been reported recently, most of them have very poor solubility to be evaluated in vivo and to be developed as potentially useful therapeutic agents. Furthermore, there were no adequate in vivo functional assays for unambiguous evaluation of their functional activity of D3 ligands at D3 receptors and their functional selectivity at the other dopamine receptors. We have recently developed and validated new in vivo functional assays that can nicely distinguish between the D3 and D2 activities. Based on novel D3 ligands we previously discovered, we have designed and synthesized a set of potent, selective D3 ligands. Our long- term goal of this project is to develop potent and highly selective D3 ligands for the treatment of drug abuse. To achieve this goal, we have assembled a multidisciplinary team consisting of investigators with extensive expertise in computational drug design and medicinal chemistry, biochemical pharmacology of dopamine receptors, and in vivo behavioral pharmacology. We will carry out the following specific aims: Aim 1. Design and synthesize new D3 ligands, based on our promising lead compounds toward achieving highly potent and selective D3 ligands with good solubility for both in vitro and in vivo studies. Aim 2. Evaluate these new D3 ligands in a panel of in vitro receptor binding and functional assays using both the native tissues expressing respective dopamine receptors and in cell lines transfected with each of the five dopamine receptors. Aim 3. (a) For the highly selective D3 ligands obtained from Aims 1 and 2, characterize their functional activity using our newly developed and validated in vivo assays;and b) for several of the most promising D3 ligands, evaluate their therapeutic potential as a new therapy for the treatment of drug abuse. Potent and selective D3 ligands with varying intrinsic activity not only will serve as powerful pharmacological tools to further elucidate the role of the D3 receptor in the reinforcement mechanism of drug addiction, but also may ultimately be developed as novel pharmacotherapies for drug addiction and dependence.